Recent studies have indicated that bone morphogenetic protein-6 (BMP-6) and its receptors are present in adult and fetal brain. BMP-6 is important in neuronal differentiation during embryonic development. The functions of this trophic factor in the adult brain are still not known. The purpose of this study was to examine the neuroprotective effect of BMP-6 in an ischemia/reperfusion injury model. BMP-6 or vehicle was injected directly into 3 sites in the right cerebral cortex 30 min before right middle cerebral artery (MCA) ligation in chloral hydrate anesthetized rats. We, and others, have previously reported that transient ligation of MCA for 60 minutes at its first bifurcation above zygomatic arch generates distal ischemia. Animals developed body asymmetry and cortical infarction 48 hours after reperfusion. We found that animals receiving BMP-6 pretreatment had less motor asymmetry, and more locomotor activity. Some animals were sacrificed 48 hours after ischemia for histological examination. TUNEL (+) cells and Caspase-3 immunoreactivity, indicative of apoptosis in the ischemic penumbra, were significantly reduced in rats pretreated with BMP-6. The volume of infarction, as measured after TTC staining, was also significantly reduced in BMP-6 pretreated rats. Taken together, our data indicate that pretreatment with BMP-6 protects against ischemia/reperfusion insults, possibly through an anti-apoptotic mechanism.